The objective of the proposed research is to investigate the mechanisms of pancreatic glucagon secretion. Attempts will be made to isolate relatively pure alpha cell tissue, which will provide a way to directly study the biochemical mechanisms of glucagon secretion. Also, the perfused rat pancreas will be used as a diabetic model to test the hypothesis that the abnormalities of glucagon secretion in human diabetes mellitus are secondary to beta cell damage. Finally, the perfused rat pancreas will be used for study of glucose control over glucagon secretion, in particular to assess whether the glucose control is exerted by a membrane receptor mechanism or by glucose metabolism. Both mechanisms may be operative.